Fluoride drying method

ABSTRACT

The invention relates to methods and apparatus for drying [ 18 F]fluoride which comprises (i) passing a [ 18 F]fluoride solution comprising water, a solvent, [ 18 F]fluoride, and a cationic counterion through a narrow bore vessel at elevated temperature such that the water and solvent are vaporised forming a vaporised component, and (ii) collecting the resulting vaporised component by condensing into a collection vessel.

The present invention relates to a method for drying [¹⁸F]fluoride andto apparatus for performing such a method.

[¹⁸F]Fluoride is generally produced as an aqueous solution, byirradiation of a [¹⁸O]water target. In aqueous form, [¹⁸F]fluoride isrelatively unreactive and so several steps are required to provide areactive nucleophilic reagent. Firstly, a cationic counterion is added,rubidium, cesium, and tetroalkylammonium salts have been used, morecommonly potassium complexed by a cryptand such as4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8,8,8] hexacosan (tradenameKryptofix 222). This step is often performed by adsorbing the targetwater containing [¹⁸F]fluoride on an anion exchange resin and elutingwith an aqueous solution of the chosen cation, for example an aqueoussolution of potassium carbonate with Kryptofix (Schlyer et al. Appl.Radiat. Isot., 1990, vol 40, pp 1-6). Secondly, the fluoride ion has tobe dried. This step is commonly done by azeotroping the aqueous solutionwith a solvent such as acetonitrile—which is straightforward andrelatively efficient. However, in the context of a radiosynthesis, it isimportant to minimise reaction times to avoid unnecessary decay of theradioisotope. ¹⁸F has a half-life of 110 minutes and ¹⁸F-labelledtracers for PET are therefore synthesised and purified within one hourof clinical use. The azeotroping step typically takes from 8 to 10minutes in an automated radiosynthesis.

Thus, there exists a need for new methods for drying [¹⁸F]fluoride whichare rapid and efficient, particularly for methods which are susceptibleto automation and can be incorporated into or used in conjunction withautomated radiosynthesis apparatus.

According to the invention, there is provided a method for drying[¹⁸F]fluoride which comprises (i) passing a [¹⁸F]fluoride solutioncomprising water, a solvent, [¹⁸F]fluoride, and a cationic counterionthrough a narrow bore vessel at elevated temperature such that the waterand solvent are vaporised forming a vaporised component, and (ii)collecting the resulting vaporised component by condensing into acollection vessel.

In contrast to the [¹⁸F]fluoride drying methods described in the priorart, the methods of the present invention are simple and easy toautomate and involve short exposure to heat. No carrier gas is requiredas the evaporated solvent itself serves to carry the vaporised componentthrough the narrow bore vessel. Following vaporisation, the vaporisedcomponent can be directed into a collection vessel, which can be sealedor open as required, and by keeping the collection vessel below theboiling point of the solvent, condensation by nature will prevent builtup of pressure. The vaporised component can be led into a collectionvessel of choice using valves, which greatly simplifies automation. Asthere is no carrier gas or reduced pressure in the system effectivecollection of the vaporised component is ensured. The method is highlyrobust as the sensitivity to temperature changes is limited and there isno need to tightly control gas flow. As the exposure of the[¹⁸F]fluoride solution to heat occurs over a very short time-perioddecomposition should be minimal. An additional benefit is the speed withwhich [¹⁸F]fluoride drying can be achieved, which only is limited to therate of vaporisation. Finally, as the total volume of the apparatus issmall, loss of radioactivity in the process is kept to a minimum.

The narrow bore vessel preferably takes the form of a tube with a narrowbore, for example an HPLC loop with no solid support packing. Theinternal diameter of the narrow bore vessel is usually in the range ofabout 1 micrometre to 1.5 mm, preferably 40 to 200 μm. It isparticularly convenient if the narrow bore vessel is open at both endsso that the crude mixture can be flushed through.

The length of the narrow bore vessel will be chosen such that it is longenough for the purification to be effected but is sufficiently short tominimise residence time in the vessel. A convenient length for thenarrow bore vessel is from about 5 cm to 50 cm long, more usually 5 cmto 20 cm and typically about 15 cm.

Suitably, the cationic counterion present in the [¹⁸F]fluoride solutionis selected from rubidium, cesium, tetraalkylammonium salts, andpotassium complexed by a cryptand such as4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8,8,8] hexacosan (tradenameKryptofix 222). The use of potassium complexed by a cryptand such as4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8,8,8] hexacosan isparticularly suitable.

Suitable solvents for use in the methods of the invention includeacetonitrile, ethanol, tetrahydrofuran, diethylether, dichloromethane,chloroform, acetone, ethyl acetate, dimethylformamide.

In one embodiment of the invention, restrictor tubes at inlet and outletof the narrow bore vessel may be used to promote the build-up ofpressure necessary for generating the vaporised component. These tubeshave a smaller inner diameter (typically 0.1-0.2 mm) than the narrowbore vessel. By choosing a longer restrictor tube for the sample inletcompared with the outlet, the flow of the distilling vaporised componentwill be guided during feeding-in of the crude mixture.

The elevated temperature used in the method is suitably in the range of80° C. to 200° C., preferably 90° C. to 200° C. In one aspect of theinvention, the elevated temperature used is such that the solventreaches a supercritical state.

The [¹⁸F]fluoride solution may be introduced into the narrow bore vesselby any convenient means, for example by injection, applying externalpressure to the narrow bore vessel using pressurised gas or heating thenarrow bore vessel to generate vapour. The flow rate of the[¹⁸F]fluoride solution is preferably in the range 0.1 to 1.0 ml/min.

Following the [¹⁸F]fluoride drying method of the invention, the[¹⁸F]fluoride may be removed from the narrow bore vessel by passing asuitable solvent down its length, alternatively the adsorbed[¹⁸F]fluoride may be used to perform a radiofluoridation reaction withinthe narrow bore vessel.

In a further aspect of the invention, there is provided a method asdescribed above, which comprises the further step of (iii) reaction ofthe resulting dried [¹⁸F]fluoride in a narrow bore vessel to form aradiolabelled compound. The narrow bore vessel used in step (iii) may bethe same narrow bore vessel as used in step (i), or a separate narrowbore vessel in fluid connection therewith.

The narrow bore vessel may be cleaned by passing a suitable solvent downits length, alternatively disposable narrow bore vessels may be used.

According to a further aspect of the invention, there is provided anapparatus for drying [¹⁸F]fluoride using the methods described abovewhich comprises a narrow bore vessel containing a [¹⁸F]fluoridesolution, said [¹⁸F]fluoride solution comprising water, a solvent,[¹⁸F]fluoride, and a cationic counterion. Suitably, the narrow borevessel is a tube with a narrow bore, such as an HPLC loop with no solidsupport packing. More suitably, the internal diameter of the narrow borevessel is in the range of about 1 micrometre to 1.5 mm, preferably 40 to200 μm.

The following example is described with reference to FIG. 1 which is aschematic of an apparatus suitable for performing a method according tothe invention.

EXAMPLE Drying [¹⁸F]Fluoride Using Distillation Distillation Apparatus

A scheme of the apparatus is shown in FIG. 1. The tubing materialconsists of standard HPLC parts. Restrictors 1 and 2 are narrow borestainless steel tubes (i.d. 0.127 mm) of 13.5 cm and 7.0 cm length,respectively. The HPLC injector loop 3 has a capacity of 1.0 mL. Theelectrical heating cylinder 4 can be heated up to 200° C. by a heatingmodule 5 with a temperature control unit 6. The gas/liquid stream wasdirected into a trapping vial of water (1.0 mL) 8 with a vent line 9.

Fluorine-18 was produced with a cyclotron using the ¹⁸O(p,n)¹⁸F reactionand ¹⁸O enriched water (30%) as target material. A stock solutionconsisting of caesium carbonate (10 mg), water (0.05 ml), acetonitrile(0.5 ml), and water containing fluorine-18 (0.44 ml, 3.3 mCi, 123 MBq)was prepared.

A syringe (1 ml, Hamilton, Gastight) 7 was filled with stock solution(0.1 mL) and air (0.9 ml). The solution was pumped with 0.2 ml/min intothe pre-heated apparatus (150° C.). The drying process was completedafter 4.5 minutes. The distilled mixture of acetonitrile and watercontained no [¹⁸F]fluoride contamination. Thus, more than 99% of thestarting ¹⁸F had been retained and dried.

The experiment was repeated twice using increased volumes of stocksolution (0.2 mL and 0.4 mL). The ¹⁸F contamination of the trapping vialwas less than 0.1% in both cases.

1. A method for drying [¹⁸F]fluoride which comprises (i) passing a[¹⁸F]fluoride solution comprising water, a solvent, [¹⁸F]fluoride, and acationic counterion through a narrow bore vessel at elevated temperaturesuch that the water and solvent are vaporised forming a vaporisedcomponent, and (ii) collecting the resulting vaporised component bycondensing into a collection vessel.
 2. A method according to claim 1wherein the narrow bore vessel is a tube with a narrow bore, such as anHPLC loop with no solid support packing.
 3. A method according to claim1 wherein the internal diameter of the narrow bore vessel is in therange of about 1 micrometre to 1.5 mm, preferably 40 to 200 μm.
 4. Amethod according to claim 1 wherein the cationic counterion present inthe [¹⁸F]fluoride solution is selected from rubidium, cesium,tetraalkylammonium salts, and potassium complexed by a cryptand such as4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8,8,8] hexacosan.
 5. A methodaccording to claim 1 wherein the solvent is selected from acetonitrile,ethanol, tetrahydrofuran, diethylether, dichloromethane, chloroform,acetone, ethyl acetate, dimethylformamide, and supercritical carbondioxide.
 6. A method according to claim 1, which comprises the furtherstep of (iii) reaction of the resulting dried [¹⁸F]fluoride in a narrowbore vessel to form a radiolabelled compound.
 7. Apparatus for drying[¹⁸F]fluoride which comprises a narrow bore vessel containing a[¹⁸F]fluoride solution, said [¹⁸F]fluoride solution comprising water, asolvent, [¹⁸F]fluoride, and a cationic counterion.
 8. Apparatusaccording to claim 7 wherein the narrow bore vessel is a tube with anarrow bore, such as an HPLC loop with no solid support packing. 9.Apparatus according to claim 7 wherein the internal diameter of thenarrow bore vessel is in the range of about 1 micrometre to 1.5 mm,preferably 40 to 200 μm.